Neural correlates of the motivational and somatic components of naloxone-precipitated morphine withdrawal

In morphine-dependent rats, low naloxone doses have been shown to induce conditioned place aversion, which reflects the negative motivational component of opiate withdrawal. In contrast, higher naloxone doses are able to induce a 'full' withdrawal syndrome, including overt somatic signs. The c-fos gene is commonly used as a marker of neuronal reactivity to map the neural substrates that are recruited by various stimuli. Using in situ hybridization, we have analysed in the brain of morphine-dependent rats the effects of acute withdrawal syndrome precipitated by increasing naloxone doses on c-fos mRNA expression. Morphine dependence was induced by subcutaneous implantation of slow-release morphine pellets for 6 days and withdrawal was precipitated by increasing naloxone doses inducing the motivational (7.5 and 15 mug/kg) and somatic (30 and 120 mg/kg) components of withdrawal. Our mapping study revealed a dissociation between a set of brain structures (extended amygdala, lateral septal nucleus, basolateral amygdala and field CA1 of the hippocampus) which exhibited c-fos mRNA dose-dependent variations from the lowest naloxone doses, and many other structures (dopaminergic and noradrenergic nuclei, motor striatal areas, hypothalamic nuclei and periaqueductal grey) which were less sensitive and recruited only by the higher doses. In addition, we found opposite dose-dependent variations of c-fos gene expression within the central (increase) and the basolateral (decrease) amygdala after acute morphine withdrawal. Altogether, these results emphasize that limbic structures of the extended amygdala along with the lateral septal nucleus, the basolateral amygdala and CA1 could specifically mediate the negative motivational component of opiate withdrawal.